α-B Crystallin Reverses High Diastolic Stiffness of Failing Human Cardiomyocytes

Abstract

Background-Cardiomyocytes with a less distensible titin and interstitial collagen contribute to the high diastolic stiffness of failing myocardium. Their relative contributions and mechanisms underlying loss of titin distensibility were assessed in failing human hearts. Methods and Results-Left ventricular tissue was procured in patients with aortic stenosis (AS, n=9) and dilated cardiomyopathy (DCM, n=6). Explanted donor hearts (n=8) served as controls. Stretches were performed in myocardial strips, and an extraction protocol differentiated between passive tension (F passive ) attributable to cardiomyocytes or to collagen. F passive -cardiomyocytes was higher in AS and DCM at shorter muscle lengths, whereas F passive -collagen was higher in AS at longer muscle lengths and in DCM at shorter and longer muscle lengths. Cardiomyocytes were stretched to investigate titin distensibility. Cardiomyocytes were incubated with alkaline phosphatase, subsequently reassessed after a period of prestretch and finally treated with the heat shock protein α-B crystallin. Alkaline phosphatase shifted the F passive -sarcomere length relation upward only in donor. Prestretch shifted the F passive -sarcomere length relation further upward in donor and upward in AS and DCM. α-B crystallin shifted the F passive -sarcomere length relation downward to baseline in donor and to lower than baseline in AS and DCM. In failing myocardium, confocal laser microscopy revealed α-B crystallin in subsarcolemmal aggresomes. Conclusions-High cardiomyocyte stiffness contributed to stiffness of failing human myocardium because of reduced titin distensibility. The latter resulted from an absent stiffness-lowering effect of baseline phosphorylation and from titin aggregation. High cardiomyocyte stiffness was corrected by α-B crystallin probably through relief of titin aggregation. (Circ Heart Fail. 2017;10:e003626.

Cellular and Molecular Differences between HFpEF and HFrEF: A Step Ahead in an Improved Pathological Understanding

“…were also partially responsible for increased Fpassive, which could increase overall cardiac stiffness [57]. Interestingly, truncated titin variants in HFrEF patients promoted cardiac functional and structural alterations [58].…”

“…In patients with HFpEF and hypertension, titin was hypophosphorylated at S4185 (PKG/PKA site in N2Bus), but hyperphosphorylated at S11878 (PKCα site in PEVK) compared to non-hypertensive HFpEF patients and control subjects [74]. In patients with HFrEF, titin dephosphorylation and aggregation ex vivo were also partially responsible for increased F passive , which could increase overall cardiac stiffness [57]. Interestingly, truncated titin variants in HFrEF patients promoted cardiac functional and structural alterations [58].…”

The BAG3-dependent and -independent roles of cardiac small heat shock proteins

“…regulates cardiac elasticity and diastolic function (82)(83)(84)(85). αB-crystallin can also translocate to the mitochondria, where it inhibits mitochondrial permeability transition pore opening, thus stabilizing mitochondrial membrane potential and inhibiting apoptosis (86)(87)(88)(89).…”

Cardiac Contractility Modulation in Heart Failure Patients. Fundamental Mechanisms and Clinical Results

“…Эта гипотеза была поддержана С. Franssen и соавт. [40], которые продемонстрировали, что αB-кристаллин снижает выраженную диастолическую ригидность поврежденных кардиомиоцитов человека, вероятно, благодаря уменьшению агрегации титина. Экспрессия sHSP регулируется воздействием магнитных полей, как это и было продемонстрировано на кардиомиоцитах для HSP70 и HSP27.…”